U.S. patent application number 10/617546 was filed with the patent office on 2004-03-18 for process for providing a stable crystalline form of salbutamol.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Brodka-Pfeiffer, Katharina, Grass, Peter, Haeusler, Heribert, Langguth, Peter, Thieme, Herbert.
Application Number | 20040052734 10/617546 |
Document ID | / |
Family ID | 30011073 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040052734 |
Kind Code |
A1 |
Brodka-Pfeiffer, Katharina ;
et al. |
March 18, 2004 |
Process for providing a stable crystalline form of salbutamol
Abstract
The invention relates to a process for providing a stable
crystalline form of a fine-milled salbutamol sulfate, which can be
produced, stored and used while maintaining the aerodynamic
properties required for inhalation thereof, which comprises the
steps of a) micronizing salbutamol sulfate into a particle size
required for inhalation; b) conditioning said salbutamol sulfate by
treatment with a water-containing vapor; and c) drying the
substance.
Inventors: |
Brodka-Pfeiffer, Katharina;
(Mainz, DE) ; Grass, Peter; (Ingelheim, DE)
; Haeusler, Heribert; (Klein-Winternheim, DE) ;
Langguth, Peter; (Biebergemuend, DE) ; Thieme,
Herbert; (Ingelheim, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
|
Family ID: |
30011073 |
Appl. No.: |
10/617546 |
Filed: |
July 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60408375 |
Sep 5, 2002 |
|
|
|
Current U.S.
Class: |
424/46 ; 23/295R;
564/349 |
Current CPC
Class: |
A61P 11/08 20180101;
A61K 31/137 20130101; A61P 11/06 20180101 |
Class at
Publication: |
424/046 ;
023/295.00R; 564/349 |
International
Class: |
C13K 001/10; A61K
009/14; A61L 009/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 12, 2002 |
EP |
02015 701.2 |
Claims
What is claimed is:
1. A process for providing a stable crystalline form of a
fine-milled salbutamol sulfate, which can be produced, stored and
used while maintaining the aerodynamic properties required for
inhalation thereof, which comprises the steps of a) micronizing by
any conventional method salbutamol sulfate into a particle size
required for inhalation, more than 90% of the particle size
distribution being less than 4.6 .mu.m; b) conditioning said
salbutamol sulfate by treatment with a water-containing vapor phase
at a temperature from 20 to 50.degree. C. and a relative humidity
from 45 to 80%; and c) drying the substance.
2. The process according to claim 1 wherein the conditioning, in
the case of a substance mixture, may be performed in a one-step
procedure or a multi-step procedure using different relative
humidity/temperature combinations.
3. The process according to claim 1 wherein step b) is carried out
at a temperature from 25 to 40.degree. C. and at a relative
humidity from 45 to 75%.
4. The process according to claim 1 wherein salbutamol sulfate
obtained in step a) has the following particle size
distribution:
5 Amount [%] Particle size [.mu.m] 10 <0.70 50 <1.53 90
<3.42
5. The process according to claim 1 wherein salbutamol sulfate
obtained in step b) has the following particle size
distribution:
6 Amount [%] Particle size [.mu.m] 10 <0.75 to <0.85 50
<1.66 to <1.80 90 <3.55 to <3.75
6. The process according to claim 1 wherein the conditioning step
b) is carried out for at least 1 hour.
7. Crystalline salbutamol sulfate produced by the process of claim
1.
Description
RELATED APPLICATIONS
[0001] Benefit of U.S. Provisional Application Serial No.
60/408,375, filed on Sep. 5, 2002 is hereby claimed.
FIELD OF THE INVENTION
[0002] The invention relates to a process for providing a stable
crystalline form of a fine-milled salbutamol sulfate, which can be
produced, stored and used while maintaining the aerodynamic
properties required for inhalation thereof, which comprises the
steps of
[0003] a) micronizing salbutamol sulfate into a particle size
required for inhalation;
[0004] b) conditioning said salbutamol sulfate by treatment with a
water-containing vapor; and
[0005] c) drying the substance.
BACKGROUND OF THE INVENTION
[0006] Micronisation is a high energy process, which induces
changes in the crystallinity of materials. Preferably salbutamol
sulphate is micronised by an air jet mill. As a result, the
crystalline structures on the particles' surface are being
destroyed and amorphous areas are formed. After micronisation of
salbutamol sulphate only small amounts of amorphous material are
produced. Nevertheless even these small amounts can have important
effects on the physical stability of the powder. The amorphous
state is thermodynamically unstable and tends to convert to the
stable, crystalline state. The recrystallisation process of
disordered regions on the particles' surface leads to agglomeration
of milled particles. It is possible, that in this case bridges are
being built between the individual particles, which leads to
particle growth. That is an undesirable process, since particles
are designed to range between 1 to 10 .mu.m in diameter in order to
exert respirative effect.
[0007] In some pharmaceutical processes such as grinding, wet
granulation, tablet compaction and spray drying, disorder of
crystal structure can occur and lead to amorphous particles or
parts thereof. These amorphous regions can be desirable, since e.g.
enhanced dissolution and a higher bioavailability may result. On
the other hand, they may be disadvantageous because they may lead
to a decrease of physical stability.
[0008] In various publications the importance of amorphous parts in
crystalline powders has been discussed [4, 8, 9]. Amorphous regions
have the rheological property of a solid state but the structure of
a liquid [7]. They are thermodynamically unstable and tend to
convert to a stable, crystalline state. Amorphous solids are in
general physically and chemically less stable than the
corresponding crystals because they are in a higher energy state
than the crystalline form and they have greater molecular
mobility.
[0009] Amorphous salbutamol sulphate may be formed as a result of
micronisation with an air-jet-mill. Depending on the level of
grinding energy, increasing portions of amorphous content may be
generated on the surface of the crystal. The powder's surface is
essential because the interaction between the amorphous region and
other phases are different than the interaction between the phases
and the material in the crystalline state.
[0010] For the crystallization process, the temperature of glass
transition (Tg) is important. Above this point the molecular
mobility is higher and therefore the re-crystallization process is
accelerated. Tg is dependent on factors such as temperature and
humidity. A greater difference between the Tg and the surrounding
temperature of the sample stabilizes the amorphous state [5].
Therefore, lowering the Tg by means of a plastisizer (in most cases
absorption of water) or increasing the surrounding temperature
decreases the energy barrier for re-crystallization.
[0011] When the re-crystallization process occurs in an
uncontrolled manner it may lead to significant problems during
storage of pharmaceutical powders, i.e. uncontrolled particle
growth. Thus the effectiveness of powders for inhalation may be
compromised.
[0012] Therefore the problem underlying the present invention was
to provide a method which allows to produce stable micronised
salbutamol sulphate in which the tendency of uncontrolled particle
growth has been minimized.
[0013] It has been found surprisingly, that stable micronised
salbutamol sulphate can be obtained, if the micronised product is
conditioned under well defined temperatures and relative
humilities.
SUMMARY OF THE INVENTION
[0014] Accordingly the present invention relates to a process for
providing a stable crystalline form of a fine-milled salbutamol
sulfate, which can be produced, stored and used while maintaining
the aerodynamic properties required for inhalation thereof, which
comprises the steps of
[0015] a) micronizing by any conventional method salbutamol sulfate
into a particle size 4.6 .mu.m;
[0016] b) conditioning said salbutamol sulfate by treatment with a
water-containing vapor phase at a temperature from 20 to 50, in
particular 25 to 40.degree. C., and a relative humidity from 45 to
80%, in particular 45 to 75%, more preferably 55 to 75%; and
[0017] c) drying the substance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 shows the isothermal microcalorimetry of a freshly
micronised powder (1) and one of a conditioned powder at a
temperature of 70.degree. C. for 5 hours (2).
[0019] FIG. 2 provides the X-ray powder diffractometry of 100%
amorphous material at different temperatures under vacuum.
[0020] FIG. 3 shows the particle size distributions of micronised,
dry conditioned (left), wet conditioned (right) and stored powder
for 4 weeks.
[0021] FIG. 4 shows the relative humidity in a PE-bag filled with a
freshly micronised salbutamol sulphate powder and stored at
relative humidity of 45%.
[0022] FIG. 5. provides the amorphous amounts of the stored (four
weeks) sample: thermal conditioned powders in a PE-bag 1.2%
(amorphous), freshly micronised powder in a PE-bag (dash) and in
PE-bag+aluminium bag (dot).
[0023] FIG. 6. shows the microcalorimetry of micronised salbutamol
sulphate upon storage in an opened TWO-Glass at room temperature
(21.5.degree. C., 42% RH): amorphous amounts after 1.sup.st week
6.5% (3), 2.sup.nd week 5.4% (2) and 4.sup.th week 4.5% (1).
[0024] FIG. 7. Shows the relative humidity of a micronised and
wrapped up sample of salbutamol sulphate stored at relative
humidity of 55%.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention relates to a process for providing a
stable crystalline form of a fine-milled salbutamol sulfate, which
can be produced, stored and used while maintaining the aerodynamic
properties required for inhalation thereof, which comprises the
steps of
[0026] a) micronizing by any conventional method salbutamol sulfate
into a particle size required for inhalation, more than 90% of the
particle size distribution being less than 4.6 .mu.m;
[0027] b) conditioning said salbutamol sulfate by treatment with a
water-containing vapor phase at a temperature from 20 to 50, in
particular 25 to 40.degree. C., and a relative humidity from 45 to
80%, in particular 45 to 75%, more preferably 55 to 75%; and
[0028] c) drying the substance.
[0029] In a preferred embodiment of the present invention the
process may be performed in a one-step procedure or a multi-step
procedure using different relative humidity/temperature
combinations.
[0030] Further preferred embodiments are processes wherein:
[0031] (A) step b) is carried out at a temperature from 25 to
40.degree. C. and at a relative humidity from 55 to 75%; and/or
[0032] (B) the said salbutamol sulfate obtained in step a) has the
following particle size distribution:
1 Amount [%] Particle size [.mu.m] 10 <0.70 50 <1.53 90
<3.42
[0033] and/or
[0034] (C) the said salbutamol sulfate obtained in step b) has the
following particle size distribution:
2 Amount [%] Particle size [.mu.m] 10 <0.75 to <0.85 50
<1.66 to <1.80 90 <3.55 to <3.75
[0035] and/or
[0036] (D) the conditioning step b) is carried out for at least 1
hour, preferably for 3 to 48 hours, more preferably for 5 to 24
hours.
[0037] Furthermore, the invention relates to a salbutamol sulfate
produced by the process according to the present invention.
[0038] Another aspect of the present invention is the use of
salbutamol sulfate produced by the process according to the present
invention for the preparation of a medicamentation for the
treatment of respiratory diseases, in particular asthma and/or
COPD.
[0039] Following conditioning the powders are stored and evaluated
at specific time intervals. For comparison, a sample of the
micronised powder is stored without a preceding conditioning
procedure and evaluated accordingly.
[0040] 1. Materials and Methods
[0041] 1.1. Materials
[0042] Salbutamol sulphate or albuterol sulphate is
.alpha.-[[(1,1-dimethylethyl)-amino]methyl-4-hydroxy-1,3-benzenedimethano-
l belongs to the class of .beta.-2-agonists and is of high
commercial interest. The chemical structure is shown in formula I:
1
[0043] As packaging materials, a polyethylen bag or a polyethylen
bag in an aluminium bag or a twist-off-Glass were used.
[0044] 1.2. Methods
[0045] 1.2.1. Milling
[0046] Micronised powders were prepared with a MC Jetmill 50
(Jetpharma, Balerna, Switzerland).
[0047] Extant room conditions were 21.degree. C..+-.1.degree. C.
and 45%.+-.2% RH.
[0048] 1.2.2. Conditioning
[0049] The micronised powder underwent different conditioning
settings in a climate chamber (Wei.beta. Klimatechnik GmbH,
Reiskirchen-Lindstruth, Germany). The temperature was set at
25.degree. C. and 40.degree. C. and the relative humidity was
varied in a field between 45% and 75%, respectively.
[0050] For "dry" conditioning settings the powders were prepared at
a temperature of 70.degree. C. in a thermal oven (Heraeus, Hanau,
Germany).
[0051] 1.2.3. Recording of Humidity
[0052] Using a humidity sensor (Ebro, Ingolstadt, Germany) the
sorption behaviour of the micronised and wrapped powder was
measured.
[0053] 1.2.4. Particle Size Analysis
[0054] The particle size distributions of salbutamol sulphate were
measured using powder laser diffraction, HELIOS-SYSTEM (Sympatec,
Clausthal-Zellerfeld, Germany). Samples were introduced through the
RODOS dry powder feeder. The supply pressure of the injector was at
3 bar. The optical concentration reached values between 4 and
8%.
[0055] 1.2.5. Particle Morphology
[0056] The morphology of salbutamol sulphate was examined by using
a DSM 926 scanning electron microscope (Zeiss, Jena, Germany). The
powders were mounted onto a plate and were sputter coated with 60
nm gold/palladium.
[0057] 1.2.6. Isothermal Microcalorimetry
[0058] The powder was investigated using a Thermal Activity Monitor
(Type 2277, Thermometric, Sweden) at 25.degree. C. The samples were
weighted into a glass ampoule and a tube was added containing a
saturated salt solution. The ampoule was sealed and equilibrated in
the calorimeter for 5 min before lowering it into the measuring
site.
[0059] 1.2.7. Powder X-ray Diffraction
[0060] The Powder X-Ray Diffraction (Bruker, Rheinstetten, Germany)
patterns were acquired at different temperatures using Cu-K .alpha.
radiation (.lambda.=1.5406 .ANG.). The data were collected over an
angular range of 2-40.degree.2.theta. using a step size of
0,014.degree.2.theta. and a step time of 2 sec.
[0061] 2. Results and Discussion
[0062] 2.1. Conditioning
[0063] 2.1.1. Conditioning with Elevated Temperature (Dry
Conditioning)
[0064] Conditioning of the micronised salbutamol sulphate at
70.degree. C. for 5 hours does not lead to recrystallisation, and
therefore no stable product. Rather, such "conditioning" conditions
are counterproductive, since due to the high temperature water is
expelled from the sample. Water, however, serves as a plasisizer
and consequently its disappearance leads to a stabilisation of the
amorphous state (increase in Tg). Therefore, no changes in the
amorphous content are observed under such conditions.
[0065] Isothermal microcalorimetry shows that the exothermal
recrystallisation process is delayed on account of the water
displacement (FIG. 1). An increase of the thermal conditioning time
up to 24 hours has no additional effect.
[0066] Particle growth is not observed following dry conditioning.
This is shown in the following Table 1.
3TABLE 1 Particle size distribution after thermal conditioning of
micronised salbutamol sulphate Micronised powder relative change of
conditioned 5 hours particle size Micronised powder by 70.degree.
C. spreading .mu.m .mu.m % 10% < 0.83 0.82 -1.2 50% < 1.94
1.90 -2.1 90% < 4.53 4.45 -1.8
[0067] Using x-ray powder diffractometry in vacuum and under
different temperatures (FIG. 2), it can be proved, that amorphous
salbutamol sulphate (produced by freeze-drying) does not
recrystallize under exclusion of humidity. Water molecules are
therefore necessary for the transformation into the thermostable
state. Consequently, minimum humidities are essential in order to
put the recrystallisation process into operation.
[0068] 3.1.2 Conditioning with Moisture (Wet Conditioning).
[0069] Relative humidities (RH)<50% at 25.degree. C. are
insufficient to achieve complete recrystallisation of amorphous
salbutamol sulphate within 24 hours. For example, conditioning of a
sample at 25.degree. C. and 45% RH for 24 hours leads to a
reduction of the amorphous fraction by 2.5% (initial sample
amorphous content of 7.7%). This can be shown by the isothermal
microcalorimetry.
[0070] When sufficient conditioning settings are employed, particle
growth occurs in each batch. This particle growth cannot be
excluded since a formation of bridges between the amorphous
surfaces takes place during the recrystallisation process.
[0071] Through selective variation of the humidity and temperature,
the percentage of particle growth in dependence on these factors
should be evaluated. A clear tendency towards stronger particle
growth can be observed by an increase of humidity. An increase of
the temperature up to 40.degree. C. with constant relative
humidities also shows a tendency towards particle growth, however,
this dependence is not very expressed (Tab. 2).
4TABLE 2 Dependence of the particle growth on the humidity and
temperature settings during conditioning relative change in
Micronised powder particle size Micronised powder conditioned
distribution .mu.m .mu.m % 24 h 55% 25.degree. C. 10% < 0.70
0.78 11.4 50% < 1.30 1.66 8.50 90% < 3.42 3.56 4.10 24 h 65%
25.degree. C. 10% < 0.70 0.82 17.1 50% < 1.53 1.76 15.0 90%
< 3.42 3.67 7.30 24 h 75% 25.degree. C. 10% < 0.70 0.83 18.6
50% < 1.53 1.77 15.7 90% < 3.42 3.69 7.90 24 h 55% 40.degree.
C. 10% < 0.70 0.79 12.9 50% < 1.53 1.68 9.80 90% < 3.42
3.59 5.00 24 h 65% 40.degree. C. 10% < 0.70 0.80 14.3 50% <
1.53 1.72 12.4 90% < 3.42 3.64 6.40 24 h 75% 40.degree. C. 10%
< 0.70 0.84 20.0 50% < 1.53 1.78 16.3 90% < 3.42 3.69
7.90
[0072] Following five hours of conditioning at 40.degree. C. and
75% RH turns a sample of the partially amorphous powder into
complete crystalline material. Additional duration of conditioning
beyond five hours shows no effect on the particle size, as does
storage under the same conditions for two weeks. These observations
reveal that the aim of the conditioning process is already reached
after five hours. Further conditioning time has no influence on the
physical stability of the powder (results not showed).
[0073] In summary it has been shown that pure thermal conditioning
is not practical and relative humidity at room temperature should
be at least 55%, so that the product is able to recrystallize
within 24 hours. This humidity level shows the smallest influence
on particle growth. If the duration of conditioning is an issue,
e.g. 40.degree. C. and 75% RH are suitable to obtain a stable,
entirely crystalline product already after five hours.
[0074] 3.2. Storage
[0075] 3.2.1. Storage Following Conditioning
[0076] The stability of the product is dependent on the methods of
conditioning.
[0077] With dry conditioning, uncontrolled particle growth up to
16% in terms of particle diameters was observed following four
weeks of storage. Wet conditioning, however, produces products
which remain stable throughout the period of storage (FIG. 3).
[0078] 3.2.2. Storage without a Conditioning Step
[0079] In order to assess particle stability without a previous
conditioning step, freshly micronised material is wrapped and
stored between 21.degree. C. and 23.degree. C. and a relative
humidity of approx. 45% for a total period of three months without
a preceding conditioning step.
[0080] After one, two and four weeks as well as after three months
a sample is collected and analysed for its particle size
distribution and amorphous content.
[0081] It can be shown that the wrapped and stored powder without
preceding conditioning, shows likewise particle growth (results not
showed).
[0082] With the help of a humidity sensor it is possible to observe
the sorption behaviour of the micronised, in a PE-bag wrapped,
powder. Approx. 30 g of the freshly grinded substance are wrapped
in a PE-bag together with a humidity sensor and afterwards closed.
Analysis of the water-sorption behaviour of micronised salbutamol
sulphate stored within a PE-bag is shown in FIG. 4.
[0083] At first there is a low relative humidity in the closed bag,
since the water molecules are being adsorbed by the amorphous areas
on the surface of the particles. Within five days ambient humidity
is reached inside the bag. Since the relative humidity is less then
50%, the process of recrystallisation takes place only at a
comparatively slow rate. The time to equilibrium is approximately
five days. The recrystallisation does not take place as a
cooperative process. Rather, the amorphous material assimilates
water, recrystallizes and the desorbed water molecules are being
assimilated by further amorphous regions. This can be interpreted
from the oszillating shape of the plot in FIG. 4.
[0084] The stored material is tested for amorphous amounts, too. A
continuous decrease of the amorphous content becomes obvious,
whereas the powder which is wrapped in a PE-bag plus an aluminium
bag shows the highest amorphous content after a period of two
weeks. After four weeks the amorphous content of the unconditioned
powder lies beneath 0.5%. The amorphous amount of the thermal
conditioned powder has still after four weeks of storage a value of
circa 1.2% (FIG. 5). FIG. 6 shows the continous decrease of
amorphous amounts of micronised powder which is stored in an open
TWO-Glass at room conditions. In this case the process of
recrystallisation is no cooperative, too.
[0085] An analogous storage experiment is carried out at the same
temperature level but at a higher humidity of 55% (FIG. 7). Here, a
clear difference in the sorption behaviour becomes evident. The
relative humidity increases up to approx. 55%, followed by a quick
recrystallisation (cooperative), desorption and adjustment of the
equilibrium-moisture content to approx. 55%. Under such conditions,
the sample is already completely recrystallized within one week.
The relative humidity reaches in a wrapped state occasionally
values of more than 90%.
[0086] In summary it can be shown that during storage of the
micronised powder a "self-conditioning" process may occur. The rate
of self-conditioning is dependent on the relative humidity. Lower
humidity leads to an extended duration of self-conditioning
process. Furthermore, when particles are stored below a relative
humidity of 50%, a significantly lower particle growth is observed
as compared to particles which are stored above this humidity
value.
[0087] 3. Conclusion
[0088] Sufficient conditioning of salbutamol sulphate ensures
complete conversion of amorphous parts into crystalline material
and stabilisation of the powder. The physical stability of the
micronised powder is influenced by the conditioning parameters.
[0089] Dry conditioning has been shown to be useless in this
regard. The relative humidity at room temperature should be at
least 55%, so that the powder will recrystallize within a period of
24 hours. This humidity level shows the smallest particle growth
under the conditions tested. When shorter conditioning periods are
desired, e.g. 40.degree. C. and 75% R.H. are alternative conditions
to obtain a stable, entirely crystalline product.
[0090] The advantage of optimized conditioning process parameters
is that every batch can be controlled to show a relatively small
acceptable particle growth. Particle growth cannot be completely
prevented, however, since bridges are being built between the
amorphous surfaces during the process of re-crystallization.
[0091] The extent of the agglomeration is dependent on the
amorphous parts and therefore on the micronisation energy, but also
on the parameters of conditioning and storage. The relative
humidity has a strong impact on the particle growth. Raised
temperature in the range of 25.degree. C. to 40.degree. C. has a
less pronounced effect, whereas conditioning time is
insignificant.
[0092] Non conditioned micronised powder undergoes a
.sub."self-conditioning" process upon storage. The kinetics of the
process is depending on the relative humidity with higher
humidities favouring faster rates.
[0093] A steady particle size growth is seen with unconditioned
product. The powder which is stored below 50% R.H. shows a
significantly smaller growth, than one which is stored above this
humidity level.
[0094] Influences of conditioning and storage may be assessed with
isothermal micro-calorimetry and the DVS-method, according to the
determination of freshly micronised material.
[0095] References
[0096] 1. Ahlneck, C., Zografi, G., 1990, The molecular basis of
moisture effects on the physical and chemical stability of drugs in
the solid state. Int.J.Pharm. 62, 87-95
[0097] 2. Briggner, L.-E., Buckton, G., Bystrom, K., Darcy, P.,
1994. The use of isothermal microcalorimetry in the study of
changes in crystallinity induced during processing of powders. Int.
J. Pharm. 105, 125-135.
[0098] 3. Elamin,A. A., Sebhatu,T., Ahlneck, C., 1995. The use of
amorphous substances to study mechanically activated materials in
the solid state. Int.J.Pharm. 119, 25-36
[0099] 4. Hancock,B., Zografi,G., 1997. Characteristics and
significance of the amorphous state in pharmaceutical systems. J.
Pharm. Sci. 86, 1-12
[0100] 5. Saleki-Gerhardt,A., Ahlneck, C., Zografi, G., 1994.
Assessment of disorder in crystalline solids. Int. J. Pharm. 101,
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[0101] 6. Sebhatu, T., Angberg, M., Ahlneck, C.,1994. Assesment of
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[0102] 7. Threlfall, T. L., 1995. Analysis of organic polymorphs.
Analyst, Vol. 120
[0103] 8. Ticehurst M. D., Rowe R. C., York P., 1994. Determination
of the surface properties of two batches of salbutamol sulfate by
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[0104] 9. Ward, G. H., Schultz K., 1995. Process-induced
crystallinity changes in albuterol sulfate and its effect on powder
physical stability. Pharm. Research, 12(5), 773-779
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